PATHWAYS OF BLADDER TUMORIGENESIS

描述：（直接取自申请）Project 4的长期目标是通过验证膀胱肿瘤有两种产生途径的假设来了解膀胱肿瘤发生的分子基础。第一种肿瘤与p16有关，常产生浅表乳头状肿瘤，有复发倾向，但不太可能进展。第二种，涉及p53，开始于原位癌，并经常进展。为了实现这一目标，我们将在转基因小鼠中开发肿瘤发生的模型系统，其中包含在人类移行细胞癌中经常观察到的癌发生改变。对这种量身定制的系统的需求来自于这样一个事实，尽管膀胱肿瘤在实验中由化学制剂产生，但触发此类肿瘤的分子机制往往是未知的，并且在分析这些肿瘤的情况下，它们很少模仿人类移行细胞癌中所见的致癌事件，即表皮生长因子受体（EGFR）， H-ras， p16和p53的变化。直到最近，还不可能将特定基因的表达定向到尿路上皮。然而，最近从尿路上皮特异性启动子uroplakin II （UPII）基因中分离出的这种启动子将使我们能够产生具有尿路上皮特异性致癌变化的转基因小鼠系。因此，我们将使用UPII启动子来驱动尿路上皮正常和活化的EGFR、活化的H-ras和p53显性阴性突变体的表达。我们还将利用cre/loxP系统特异性灭活小鼠尿路上皮中的p53和p16。这些转基因对尿路上皮生长和肿瘤形成的影响将被研究。为了最大限度地提高肿瘤产量，这些基因也将以特定的组合使用，如有必要，还将与亚致癌剂量的膀胱癌物质一起使用。为了评估这些改变在膀胱肿瘤中的关键作用，我们将分析适当的通路是否被激活。这些肿瘤发生的模型系统和膀胱癌发病机制的双途径假说的验证，将有助于更好地了解膀胱癌的发病机制，也可能有助于更好地了解人类移行细胞癌的治疗方法。

Description: (Taken directly from the application) The long term goal of Project 4 is to understand the molecular basis of bladder tumorigenesis by testing the hypothesis that there are two pathways that can produce a bladder tumor. The first, where p16 is involved, frequently produces superficial papillary tumors with a tendency to recur, but unlikely to progress. The second, which involves p53, starts as a carcinoma in situ and frequently progresses. Towards this goal, we will develop model systems of tumorigenesis in transgenic mice, which contain oncogenetic alterations frequently observed in human transitional cell carcinoma. The need for such tailored system comes from the fact that, although bladder tumors have been experimentally produced by chemical agents, the molecular mechanisms triggering such tumors are frequently unknown, and in the cases where they have been analyzed, they rarely mimic the oncogenic events seen in human transitional cell carcinomas, i.e., changes in epidermal growth factor receptor (EGFR), H-ras, p16 and p53. Until recently, it had been impossible to direct the expression of a gene specifically to the urothelium. However, the recent isolation of such a urothelial specific promoter, from the uroplakin II (UPII) gene, will enable us to generate transgenic mouse lines with specific oncogenic changes in the urothelium. We will therefore use the UPII promoter to drive the urothelial expression of normal and activated EGFR, activated H-ras, and a dominant negative mutant of p53. We will also utilize the cre/loxP system to specifically inactivate p53 and p16 in the mouse urothelium. The effects of these transgenes on urothelial growth and tumor formation will be examined. To maximize the tumor yield, the genes will also be used in specific combinations and, if necessary, together with subcarcinogenic doses of bladder carcinogens. To assess the crucial role of these alterations in the bladder tumors, we will analyze if the appropriate pathways are activated. These model systems of tumorigenesis and the test of the two pathway hypothesis of bladder cancer pathogenesis should lead to a better understanding of the pathogenesis of bladder tumors, and it may also contribute to a more informed therapy of human transitional cell carcinoma.